Research Pharm and Tock (6) ne 2015 ISSN 0974-3618 (Print) www.rjptonline.org NBIPT. REVIEW ARTICLE Rectal suppository as an effective alternative for oral administration Vijay D. Havaldar'*, Adhikrao V. Yadav", Remeth J. Dias!, Kailas K. Mali', Vishwajeet 8. Ghorpade’, and Nitin H. Salunkhe! YSPM’s, YTC, Faculty of Pharmacy, Wadhe, 415011 India 2GIPER, Limb, Satara, India *Coresponding Author E-mail: vdk2006@rediffmail.com ABSTRACT: Rectal route is an effective alternative for oral administration of drugs in pediatric and geriatric patient. Rectal suppository may have influence on bioavailability and may produce sustained release of drugs, Suppository avoids the complications associated with oral delivery of drugs such as frst pass effect, degradation of drugs by gastric enzymes, etc. Previous studies implicated that suppositories produced local effects but recently most interesting publications claimed that these are also producing systemic effects. Since last two decades research is focused to improve bioavailability of drugs from suppositories. The conventional solid suppositories have suffered from disadvantages such as feeling of alien, pain and discomfort. Therefore, liquid suppositories were developed which overcame the disadvantages associated with solid suppositories such as leakage from anus, avoidance of first pass effect and irritation, The selection of appropriate mucoadhesive polymer, surfactant and suppository base may influence the bioavailability and sustained release of drugs. The current review concem the physiological, biopharmaceutical characteristics of rectum and pharmaceutical related factors affecting bioavailability, suppository bases, bioadhesive polymers, and surfactant. It also covers evaluation parameters for solid and liquid suppositories. KEY WORDS: Suppository; Bioavailability; First-pass effect; Mucoadhesion; Sustained release INTRODUCTION: Rectal route is the efficient and economical method for the patients who have difficulty in swallowing especially in children and some adults, This route is beneficial in certain conditions like nausea, vomiting, inflammatory bowel diseases and hemorrhoids where parenteral and ‘oral administration of drug is not possible’. This route offers the advantage of being relatively painless. Sometimes this route is an effective alternative for oral ‘and intravenous dosage forms e.g. in vomiting, the oral administration of antiemetic drug such as ondansetron requites two daily doses? ‘Though the oral route is the route of choice for most of drugs it is not suitable for the pediatric and geriatric patients. The oral absorption of drugs mainly depends on the various factors such as gastrointestinal environment like gastrointestinal pH, gastrointestinal enzymes, gastric emptying time and intestinal transit time, ionie conditions of drugs, nature of drugs, first pass effect, ete’. Also, the injectables are not preferred by the patient ‘due to pain and safety issues. e. g. in diabetes patient ‘may complain about the physical and psychic pain due to atrophy or hyper atrophy of the subcutaneous fats at the site| of injection, Therefore, administration of medicaments by the rectal route is preferable. During. last twenty years, suppositories were not well accepted ‘due to the cultural or emotional points of view. Initially, it was used for the administration of local anesthetics, Received on 11.04.2018 Modified on 21.04.2015 ‘Accepted on 11.05.2015 © RIPT All ight reserved ‘Resear J Pharm. ard Tech 8(0: ne, 2015; Page 738-766 DOK: 10.59S810974-60X.2018.001225 astringents, antiseptic, emollient, hemorrhoids, vermifugal, and laxative agents to produce a local effect’, Salunkhe et al developed mucoadhesive microsphere based suppository formulations of _gtanisetron hydrochloride (GH) by fusion method. They 759Research Pharm and Tock (6) ne 2015 used combination of xanthan gum and sodium alginate in ‘2 hydrophilic and lipophilic polymer base’. They found that suppositories containing xanthan alginate microspheres isan effective alternative to oral dosage forms as it sustains the GH release, avoids first pass metabolism, and can be efficiently used in the ‘management of emesis in cancer chemotherapy and radiation therapy. But now days a variety of natural and synthetic drugs are formulated in the form of suppositories 10 produce @ systemic effect such as hypnotics, tranquilizers, antispasmodies, etc. Also, the suppository may be useful as a sustained release formulation for the long treatment of chronic diseases such as hypertension, asthma, diabetes, anemia, AIDS, ete", Mokhtar and coworkers developed antihypertensive suppositories of atenolol in hydrophilie bases of polyethylene glycol (PEG), or hydrophobic emulsifying bases such as witepsol H15 (WHI5) nonionic surfactant span 60 (Sp 60) with or without cholesterol (CH) and HPMC 400Cp’. They found that the arterial blood pressure lowered in six hours and persisted at normal levels within 6b, Further, suppositories have application in post operative pains. Therefore, administration of medicaments in the form of suppository is the preferable route of ‘administration due to the advantages that include: a) improved enzymatic drug stability b) higher drug content ©) constant and static environment of rectum d) avoidance of overdosing e) improved patient compliance £) avoidance of first pass elimination’ A conventional suppository is a semisolid dosage form ‘meant for insertion into body cavity that melts or softens ‘at body temperature. It is acceptable dosage form for infants, children and unconscious patients. A- major advantage of suppositories over oral dosage forms is that it docs not undergo the first pass effect in the gastrointestinal tract and liver. However, the conventional solid suppositories suffer from disadvantages such as feeling of alien, discomfort and therefore, refusal by the patient. If such solid suppositories without mucoadhesivity reach the end of colon, drugs may undergo the first-pass effect. The problem of conventional solid suppositories can be ‘overcome by developing a liguid suppository whieh: (1) forms a gel at body temperature; (2) has a suitable gel strength not to be leaked out from the anus after ‘administration; and (3) has a suitable bioadhesive force s0 as not to reach the end of the colon’, Choi and coworkers fabricated ibuprofen loaded liquid suppository using eutectic mixture system with menthol and poloxamer P 188 as a base and noted that the eutectic mixture with menthol improved the solubility of ibuprofen and such suppositories could be inserted into the rectum of rats without difficulty and leakage" Further, they suggested that drug from liquid suppository ‘could be more absorbed than that from solid one in rats. Mucoadhesive polymers have recently gained interest among pharmaceutical scientists as a means of improving drug delivery by promoting residence time and contact time with the mucous membranes. Barkat developed and evaluated rectal etodolac poloxamer gel system composed of poloxamer and bioadhesive polymers!’. They concluded that in situ gelling suppository with etodolac and mucoadhesive polymers such as microcrystalline cellulose and earbopol was safe, ‘convenient and effective dosage form of etodolac. In this review, attempts are. made to discuss effective administration of drugs, It focuses on rectal bioavailability of drugs, factors influencing bioavailability, role of surfactant and mucoedhesive polymers in enhancing bioavailability, It also highlights ‘on suppository bases, evaluation parameters for solid and liquid suppositories. BIOAVAILABILITY SUPPOSITORIES: 1) Physiology and biopharmaceutical charact of rectum: Human colon consists of ascending, descending, transverse and sigmoid colon, Sigmoid colon tums ‘medially and downward into the rectum and anal canal. ‘The rectum is about 13 em long and the anal canal is of few centimeters of the colon that surrounds the anus. The terminal end of colon is usually referred as rectum clinically", The rectum has relatively small absorption surface 0,02-0,05m? and is characterized by absence of villi" Viscous rectal fluid (0.5 - 1.25mi) spread over the surface having pH 7.4 with a low buffer capacity. ‘The rectum is usually empty except when fecal matter arzives from higher part of the colon temporarily. This ‘material is either expelled or transported back into colon, ‘depending on the voluntary control exhibited by the anus sphincter. A drug has greater opportunity to make ‘contact with the absorbing rectal surface in the absence ‘of fecal matter. Other conditions such as diarthoca, colonic obstruction and tissue dehydration can influence the rate and degree of drug absorption from rectal site" Absorption of drug from rectal suppositories depends on diffusion of drug to the site of rectal mucosa. The diffusivity of drug depends on nature of drug and physiological state of the colon that is amount and ‘chemical nature of fluids and solids present, The rectum is usually empty except when fecal matter arrives from higher part of the colon temporarily, This material is cither expelled or transported back into colon, depending ‘on the voluntary control exhibited by the anus sphincter. A drug has greater opportunity to make contact with the absorbing rectal surface in the absence of fecal matter Other conditions such as diarrhoea, colonic obstruction and tissue dehydration can influence the rate and degree ‘of drug absorption from rectal site, Rectal administration of drug avoids partly hepatic first-pass elimination. The OF DRUGS FROM es 760Research Pharm and Tock (6) ne 2015 superior rectal vein and middle rectal vein are connected to the portal system and inferior rectal vein is directly ‘connected to inferior vena cava thus entering drug into the systemic circulation’, However, there is no sharp distinction between these venous drainages, since the rectal veins are linked by an extensive anastomoses network. With this route, 50-70% ofa drug suitable for rectal administration is absorbed. In one study, it was observed that on lidocaine, avoided hepatic first-pass elimination following rectal administration of the drug" Systemic availability was found to be increased by almost 100% following rectal administration compared With the oral route for the same dose. The absorption of drug through rectal administration is related with pH partition theory. Thus, rectal absorption involves simple diffusion process through the lipoidal membrane, Physico-chemical and physiological properties may have influence on permeability of drugs across the intestinal epithelium and may differ in various intestinal regions" Permeability of drug across the rectum depends on mucosal area, fluid volume and pore size. In rectum, absorption of water is low as compared to other parts of the gastrointestinal tract". This is due to smaller pore radius, tighter epithelium, less fluidity in the rectal ‘membrane, lower number of pores in the rectal region, ‘and decreased mucosal surface area. There is @ difference in the transport of electrolytes and water. ‘These are transported transcellularly inthe colon’ rectum that is different from more high permeable tissue in which the transportation of electrolytes takes place by the paracellular route". It was observed that an unstirred water layer is an essential factor as it may be thick and ‘more coherent in the colonic-rectal region in the jejunum, of human, In suppository where drug. substance dissolves or disperses in the vehicle, the absorption may depend on the particle size, solubility in water and partition coefficient. In other cases where drugs dissolve cither fully or in parts in base the absorption will depend on solubility in the base, water distribution coefficient and relative phase volume ratio”, According to Kakemi, drug may be absorbed only when it is dissolved ‘completely in aqueous rectal fluid as there is a litle absorption of drug from the oily solution, If My is the amount of drug in oil and M, is amount of | ‘drug in water and @ is a relative phase volume rato, then the release of drug from suppository will be represented by the following equation M, = My! (K ®) Where K is the partition coefficient Above equation describes the equilibrium conditions. If the rate of partioning of drugs is slower than the absorption from aqueous phase, equilibrium will never be reached. In such situation, rate determining process Will be transfer of drug from oil to water. Hence, for in vitro drug release sink conditions should be maintained The larger volume of dissolution medium will be requited for tansportation of dissolved drug from ‘molten mass so that it will provide an adequate area of ccontact between two phases in order to make release kinetics to in vivo. A fat-like base should be used for a water-soluble drag and a hydrophilic base for water insoluble drug. Diffusion rate of a drug suspended in 3 fat base having low hydroxyl number and viscosity is increased, 11) Pharmaceutical aspects related to bioavailability: Rectal absorption of drug through suppository involves a chain of effects leading to the bioavailability of the drug. ‘The sequence of such drug absorption from the anorectal area can be represented as follows: Drug in vehicle—» Drug in colon fluids. —» Absorption through the rectal mucosa Drugs should be released from suppository and distributed by surrounding fluids to the sites of absorption so that it will be available for absorption, A. suppository will either dissolve in the rectal fluid (water- soluble bases) or melt on the mucous layer (fatty bases) depending on the character of its vehicle ) Particle size, solubility in water and interfacial tension: Drug absorption by rectal route is governed by particle size, solubility in water and interfacial tension. Process ‘of release of drug from suppository involves the various steps such as melting, spreading, sedimentation, wetting and dissolution, Usually, absorption of drug depends ‘on the rato of dissolution which is related to the particle size, Smaller the particle size better will be the absorption as smaller particle size increases the surface area which increases the rate of dissolution, In suppository, drug should have particle size less. than 501m, In Suppository, though the smaller particle size of ‘drug does not increase the blood levels but for its dissolution in the rectal fluid requires smaller particle size, For the release of an insoluble drug from vehicle, larger particles of drug which are soluble in the rectal fluid will be preferred to increase its transport rate. Surface properties of the drug particles is an important ‘consideration in evaluation of rate of drug release as ‘drug particles in suppository dosage form transfers from ‘one phase to another. If drug particles do not wet in the vehicle or base, it may agglomerate, which in tum may affect the uniformity of dispersion of drug particles. It may occur due to the increased tendency for the agglomerated powder to sediment prior to the setting of 761Research Pharm and Tock (6) ne 2015 suppository. Therefore, itis necessary to add surfactant to formulation to reduce the surface effects of poorly Wettable drug particles and to improve the wetting of drug particles that will facilitate dissolution of drug in the suppository and in rectal fluids. li) Hardening effect: Hardening effect leads to inercase in the melting time of suppositories. It occurs during storage of suppositories. This effect arises in bases with higher melting ranges (Witepsol H37, 36-38°C). Minor changes occur in bases ‘with the lowest melting points (e.g. Witepsal H 32, 31- 32° C), It can be inhibited by the addition of 2% soya lecithin. It is considered that hardening effect oceurs due to polymorphic phase transitions, increase in crystallinity ‘and_transesterification, Crystallization of polymorphs ‘can be prevented by blending suppository bases with surface-active agents in optimum concentrations as at higher surface-active agent concentrations produce retardant andlor ievitative effects. Varnshey and coworker studied effect of different surfactants such as sodium lauryl sulphate, span 60 and 80, tween 60 and 80 ‘and sodium tauchocholate on the release pattern of cocoa butter suppository containing flurbiprofen sodium" They observed that on addition of surface active agents to the formulation enhanced the drug release with respect to surfactant which can be arranged as- SLS > Span 80 > Tween 80 > Tween 60 > Sodium taurocholate > Span 60 > cocoa butter Suppository bases Suppository bases must melt, soften or dissolve in order to facilitate or promote the release of drug in such way that it is readily available for absorption’. A chemical ‘and/or physical interaction betwoen drug and base may influence the stability and/or bioavailability of drug, Potential chemical and/or physical interactions between ‘2 drug and the components of a formulation should be investigated during preformulation studies and in the carly stages of formulation development. The base may imitate mucous membranes and initiate a colonic response thus promoting unwanted bowel movements resulting in the expulsion of the dosage form, thereby negating any potential drug absorption via the rectal route. The spreading of suppository base with a suspended drug in the recto colon is dependent on the pressure exerted through rectal wall by abdominal ‘organs and/or by rectal wall muscles. The final spreading area decreases with increasing apparent viscosity of the spreading system”. ‘There are two types of suppository bases, oleaginous bases and water miscible bases. Oleaginous bases Fatty bases melt at body temperature. Cocoa butter (CB) is the most commonly used oleaginous suppository base but it poses several technical challenges with respect to the manufacture of dosage forms of suitable quality”. It thas several disadvantages such as it can become rancid ‘due to oxidation of the unsaturated glycerides, melt in ‘warm weather and liquefy when incorporated with certain drugs. It does not contain emulsifiers and therefore does not take up large quantities of water, As CB can easily melt and become rancid, it must be stored in cool, dry place and protected from light. CB exhibits marked polymorphism (the ability to exist in different crystalline forms, namely «, B, B’ and y), # phenomenon probably attributed to the high proportion of unsaturated triglycerides". The most stable B form is preferable for suppositories. The formation of the various crystalline forms depends on the conditions and degree of heating and cooling. Prolonged heating above 36°C leads to the formation of the unstable crystal with lower melting points. Lo and coworkers formulated thermogelling and bioadhesive liquid suppositories of epirubicin using varying concentrations of polyacylic acid (PAA) and pluronic®, Also, they prepared solid suppositories using the same concentrations of PAA and pluronic in cocoa butter base. They found that solid suppositories prepared ‘with cocoa butter base melted and gelled instantly in the rectum. It remains adhered to the mucous membrane and sustained release of drug. Further, they stated that cocoa butter has antioxidant property, which granted it a storage life of two to five years and thus protected the enclosed PluPAAJEpi mixture, Semi-synthetic fats are usually white, brittle, solid, odorless and unctuous to touch and produce suppositories that are white and have an attractive, clean, polished appearance. Hard fats are available in a variety of grades with different melting ranges, hydroxyl values and other physicochemical characteristics. Examples of somi-synthetie fatty suppository bases that are available ‘commercially include fractionated palm kernel oil B.P and hard fats such as Massa Estarium®®, Massupol®, Suppocire® and Witepsol®, Kamalinder S et al., developed suppocire based solid suppositories of paracetamol with the help of additives such as sodium lauryl sulfate (SLS), dioctyl sulfosuccinate (DOSS), Labrasol, lecithin, Miglyol 812, aerosil, Capryol PGMC. (CPGMC) and span 80 and they found that addition of | DOSS and aerosil showed prolonged drug release whereas newly used Labrasol and C PGMC exhibited auch faster release™, Water miscible bases Macrogol or polyethylene glycols (PEGs) are amongst the most widely used hydrophilic polymer suppository bases, PEGs are polymers of ethylene oxide and water, prepared in a variety of chain lengths, molecular weights 762Research Pharm and Tock (6) ne 2015 ‘and physical states", PEGs with a molecular weight ranging between 200 and 600 exist as liquids and, as the molecular weights inerease to above 1000; they exist as wax-like solids, In addition, as the molecular weights increase, their water solubility and hygroscopicity decreases. The wide range of melting points and solubilities make possible the formulation of suppositories with various degrees of heat stability and ‘with different dissolution rates. PEGs of different molecular weight can be combined to achieve @ suppository base of desired consistency and that can achive a specific drug release rate profile. The use of hhigh melting point solids as suppository bases permits convenient storage of the suppositories without the need for refrigeration and without the danger of excessive softening in warm climates. PEGs have inherently good solvent properties that may result in the retention of a ‘drug in the liquefied base, in the rectum with the potential for a reduction in therapeutic activity. If the ‘drug is party in solution and partly in suspension there is 4 high potential for erystal formation, which may cause the formulation to become brittle and prolong dissolution time, PEG bases are hygroscopic and therefore attract ‘water, resulting in a painful sensation for the patient. It is therefore recommended that suppositories manufactured from these bases should be moistened with water prior to introduction into rectum to minimize local irritation PEG bases have several advantages over synthetic and semi-synthetie suppository bases, in particular with respect to stability against oxidation and other degradation processes, their inert nature and a high water absorbing capacity. Unlike __glycerol-gelatin suppositories, PEG suppositories do not adhere to moulds and contract sufficiently on cooling to make ‘mould lubrication unnecessary during manufactur. However, PEG suppositories may become brittle, unless poured at the lowest temperature possible, but this may be overcome or reduced by the addition of surfactants or plasticizing agents such as propylene glycol to the formulation. Tarimici N et al., prepared witepsol H1S| ‘and PEG mixture (PEG 400, PEG 1000, PEG 2000 and PEG 4000) based indomethacin sustained release solid suppositories using cellulose acetate phthalate and Eudragit RL and RS in 1:1 ratio and they found that formulations containing combinations of PEG 400 and PEG 4000 as well as PEG 1000 and PEG 4000 and Eudragit mixture exhibited sustained release effect”. Surfactants Surfactants can inerease and decrease drug absorption rate, For instance, in case of sodium iodide, absorption is accelerated in the presence of surfactants and appears to be proportional to the relative surface tension lowering of the vehicle. Riegalman and Crowell showed that the rate at which drug diffuses to the surface of suppository ‘depends on the particle size of suspended drug and the presence of surface active agents that affect drug release from suppositories, In addition, they suggested that the acceleration of sodium iodide absorption might also be attributed to the mucus peptizing action of the vehicle. ‘The rectal membrane is covered by a continuous blanket, which may be more readily washed away by colonic fluids that have reduced surface tension. The cleansing action caused by the surfactant-containing vehicle may make additional pore spaces available for drug absorption, thus facilitating drug movement across the rectal membrane barrier, In case of phenol-type drugs, albsorption rate is decreased in the presence of surfactant, probably because of the formation of a drug surfactant ‘complex, Several nonionic surface active agents, closely related ‘chemically 10 the polyethylene glycols, have been developed as suppository bases”. Many of these bases ‘can be used for formulating both water soluble and oil soluble drugs. The most commonly used surfactants in suppository formulations are the polyoxyethylene sorbitan fatty acid esters (tween), polyoxyethylene stearates (Mytj), and the sorbitan fatty acid esters (Span and Arlacel), Caution should be taken while using surfactants with drugs. It has been reported that surfactants increased rate of drug absorption” ", Other reports suggested interaction of surface active agents with drugs that may Tead to decrease in therapeutic activity”. Each formulation must be tested in vivo to evaluate its medicinal effectiveness, as well as safety Gross and Becker recommended a water dispersible, hhigh melting point (50° C) suppository base consisting of polyoxyethylene 30 stearate (Myr) 51), water, white wax and dioctyl sodium sulfosuecinate (Aerosol OT)". The use of aerosol OT in the formula was claimed to lend synergism to the surfactant and thus aid in rapid disintegration of suppository. Drugs like phenobarbital, ‘quinine hydrochloride, tannic acid, and chloramphenicol were studied. Ward designed’ suppositories using polyoxyethylene sorbitan derivatives (Tweens) to melt at body temperature into liquids that disperse readily in the body fluids: Poloxamer is used as a base for liquid suppositories Being non ionic surfactant, it is a copolymer of poly (oxyethylene)-poly (oxypropylene)- poly(oxyethylene. Poloxamer solutions are known to exhibit the phenomenon of reverse thermal gelation thus remaining as solution at low temperature and gelling when lemperature increases. Furthermore, poloxamers. were reported not to cause any damage on mucosal ‘membranes"*', Several attempts have been to modulate the gelation temperature of poloxamer-based. liquids ‘The gelation temperature of poloxamer solutions was adjusted by modifying cross-linking agents and monomers by mixing the different series of poloxamers, by changing the weight of poloxamers, or by changing the pH and the ionic strength". However, most 763Research Pharm and Tock (6) ne 2015 previous studies have been focused on modulating only the gelation temperatures of poloxamer solutions. There hhas been a lack of knowledge on the strength and the bioadhesive force of gelled poloxamers, although these ‘wo factors are crucial in designing desirable liquid suppositories which do not leak out from the anus and do not reach the end of the colon after administration, Kim CK et al., developed not only temperature-sensitive but also mucoadhesive liquid suppositories containing acetaminophen using poloxamers and bioadhesive polymers and investigated their effect on rectal mucous lining, gelation temperature, gel strength and bioadhesive forces Bioadhesive Polymers Bioadhesive polymers are generally hydrophilic ‘macromolecules that contain anionic charges and strong hhydrogen bond forming groups (hydroxyl, oxide and carboxyl groups) with high molecular weight, sufficient chain flexibility and surface energy properties favoring. spreading onto mucus”. It includes synthetic polymers such as poly (acrylic acid) (PAA), hydroxypropyl ‘methylcellulose and poly (methylacrylate) derivatives, as ‘well as naturally occurring polymers such as hyaluronic acid and chitosan®, Poly (acrylic acid) is considered as a ‘good mucoadhesive but due to a high transition temperature and higher interfacial free energy, it cannot ‘wet the mucosal surface to the optimal level which may lose interpenetration and inter diffusion of the polymer. ‘These properties can be improved by copolymerizing with polyethylene glycol (PEG) or poly (vinyl pyrrolidone) (PVP). El- Leithy at al., prepared HPM and carbopol 934 hydrogels containing diclofenac sodium chitosan microspheres for rectal administration and they suggested microspheres allowed adhesion to the rectal mucosa for subsequent controlled release behavior swith no burst! Evaluation of Suppositories Solid suppositories “Appearance For testing the appearance, randomly selected suppositories cut longitudinally and examine the surfaces with naked eye™. Weight variation test Weigh individually twenty suppositories and determine the average weight. Compare the individual weights with the average weight, No suppository should deviate from average weight by more than 5% except two that may deviate by not more than 10%" Liquefaction / softening time For determination of liquefaction / softening time, 2 simple apparatus can be fabricated in the laboratory. ‘Take a burette with broken stop-cock and cut suitably so that it has a narrow opening on one side and broad ‘opening on another side, Dip the burette in hot water ‘maintained at 37" C so that narrow end faces towards hot water. Introduce the sample suppository from the top of the burette through broad end and carefully push down its length until it reaches narrow end. Insert a glass rod ‘weighing 30 g and 45 cm in length so that it rests over the suppository, Record the time at which glass rod reaches the narrow end after complete melting of suppository represents the liquefaction time. Micro-melting range test For micro-melting range test, fill the formulation to about 1 em height in eapillary tubes of 10 em length and ‘dip in a beaker containing water", Raise the temperature slowly and record temperature at which the mass liquefies was recorded, In vitro Dissolution Studies In vitto dissolution studies of suppositories are carried ‘out in USP XXIII tablet dissolution test apparatus (Electrolab TDT — O6N) employing a basket stitrer®. A specified volume of phosphate buffer pH 7.4 is used as a dissolution medium maintained at 3720.5° C, Liquid suppositories Gelation temperature Gelation temperature is determined by using the tube tilting method". Transfer 2 ml aliquot of gel to test tubes immersed in a water bath at 4°C and seal with aluminum foil, Increase the temperature of water bath in increments of 1°C and allow to equilibrate for 5 min at each new setting. Examine samples for gelation, which is said to hhave occurred when the meniscus would no longer move upon tilting through 90°C. Measurement of gel strength ‘The gel strength is determined according to the method adopted by Kim ct al. Put 50 g of liquid suppository in a 100 ml graduated eylinder and gel in a thermostat at 37°C. Place the apparatus for measuring the gel strength (weight 35 g) into the liquid suppository. Determine gel strength by the time in seconds that apparatus take to penetrate 5 em down through the gel Determination of the mucoadhesive force The mucoadhesive force, the detachment stress of the liquid suppositories is determined using a modification ‘of the mucoadhesive force-measuring device used by Choi etal. Cuta section from the fundus of rabbit rectum, and secure instantly with the mucosal side out into each ‘lass vial. Store the vials at 36.5°C for 10 min. connect ‘one vial to the balance and fix other with the poloxamer gel added and adjust the height so that the gel is placed between the mucosal sides of both vials. Allow water from a burette to fall in a beaker at a constant rate of 10 mgisec, Add increasing weight of water gradually that will detach the two vials. Determine mucoadhesive 764Research J Pharm and Teck 8(6-hne 2015, force, the detachment stress (dynciem*), from the REFERENCES: ‘minimal weights of water that detach 2 vias. u In-vivo tests experiments Male Sprague-Dawley rats are used for in vivo studies 2 having a weight of 250 + 20 g. those rats are fasted for 24-36 h prior to the experiments but allow free access 10 water’ . Divide fifteen rats into two groups, Use one group as control and administer 15g liquid suppositories containing drugikg into the rectum 4 em above the anus through a stomach sonde needle. Block the entrance of the anus with a cyanoacrylate adhesive to prevent leakage of preparations from the anus during the pharmacokinetic experiment as it may lead to inaccuracy 5. in pharmacokinetic data. Collect half milliliter of blood from the right femoral artery at various intervals and centrifuge at 3000 rpm for 10 min, Mix plasma (0.05 ml) with 0.4 ml of acetonitrile solution containing Mufenamic acid (0.5_giml), as an internal standard”. Centrifuge at 3000"rpm for 10 min to 7, precipitate the proteins. Evaporate the supematant layer (04 ml) under N2 (g). Reconstitute the residue in SOL ‘of mobile phase and then analyze, the resulting solution by HPLC equipped with an Inertsil ODS-3 C18 columa (GL svience, 0.5 jm, 15 em x 0.46 em id) and UV Jetector. The mobile phase should be acetonitrile and phosphate buffer (pH 3.5) (4:6, volume ratio). Monitor the eluent with a flow rate of 1.2 ml/min at a specified wavelength, Kosior A prepared rectal suppositories with chorpropamide alone and chlorpropamide in the dispersion system with urea using @ mixture of witepsol HIS and H19 and polyoxyethylene glycol as bases. The! developed formulations were tested on the rabbits and compared with the commercial tablets. of 12. chlorpropamide™. Finally, he concluded that the suppositories prepared with witepsol 115 along with the © dispersed chlorpropamide caused much higher decrease ‘of blood glucose levels than the commercial tablets. CONCLUSION: Rectal route is an effective alternative for oral drug 4s administration, Suppositories formulated by using ‘mucoadhsive polymers play a vital role in enhancing the bioavailability of drugs. 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